FANCD2 limits acetaldehyde-induced genomic instability during DNA replication in esophageal keratinocytes.

Individuals with Fanconi anemia (FA), a rare genetic bone marrow failure syndrome, have an increased risk of young-onset head and neck squamous cell carcinomas (SCCs) and esophageal SCC. The FA DNA repair pathway is activated upon DNA damage induced by acetaldehyde, a chief alcohol metabolite and one of the major carcinogens in humans. However, the molecular basis of acetaldehyde-induced genomic instability in SCCs of the head and neck and of the esophagus in FA remains elusive. Here, we report the effects of acetaldehyde on replication stress response in esophageal epithelial cells (keratinocytes). Acetaldehyde-exposed esophageal keratinocytes displayed accumulation of DNA damage foci consisting of 53BP1 and BRCA1. At physiologically relevant concentrations, acetaldehyde activated the ATR-Chk1 pathway, leading to S- and G2/M-phase delay with accumulation of the FA complementation group D2 protein (FANCD2) at the sites of DNA synthesis, suggesting that acetaldehyde impedes replication fork progression. Consistently, depletion of the replication fork protection protein Timeless led to elevated DNA damage upon acetaldehyde exposure. Furthermore, FANCD2 depletion exacerbated replication abnormalities, elevated DNA damage, and led to apoptotic cell death, indicating that FANCD2 prevents acetaldehyde-induced genomic instability in esophageal keratinocytes. These observations contribute to our understanding of the mechanisms that drive genomic instability in FA patients and alcohol-related carcinogenesis, thereby providing a translational implication in the development of more effective therapies for SCCs.

Potential communicative acts in children with autism spectrum disorders.

OBJECTIVE: To describe potential communicative acts in a sample of 17 children with autism spectrum disorders who produced few to no intelligible words (mean age = 32.82 months). METHODS: Parents reported on children's potential communicative acts for 10 different communicative functions. A potential communicative act was defined as any behavior produced by an individual that may be interpreted by others to serve a communicative purpose. RESULTS: Significant associations were found between higher number of gesture types and increased scores on language comprehension, language expression, and non-verbal thinking measures. Relative to other types of potential communicative acts, parents reported that children used higher proportions of body movement. CONCLUSION: Number of body movement types was not related to child ability, while number of gesture types was related to receptive and expressive language. Findings underscore the link between language and gesture, and offer support for an ecological systems perspective of language learning.